Founded in 1999, Adenosine Therapeutics LLC (ATL) is a drug discovery and development company that has developed a family of potent and selective adenosine A2A receptor agonists. With the help of STTR funding, ATL has developed a lead adenosine A2A receptor agonist, ATL-146e, that is currently in late Phase II of clinical development for use as a coronary vasodilator in cardiac stress imaging. The central goal of this project is to further the clinical development of ATL-146e for prevention of cardiac reperfusion injury that occurs in patients with evolving acute myocardial infarction (AMI) who undergo revascularization with primary coronary stenting. AMI is the leading single cause of death in the US, accounting for 500,000- 700,000 coronary-artery disease-related deaths annually and for which only one therapeutic intervention is approved. We have demonstrated that ATL-146e protects against ischemia-reperfusion injury in liver and kidney, as well as in mouse, rabbit and canine models of coronary ischemia-reperfusion injury. The safety of ATL146e in man has been established during bolus administration that is used for pharmacological stress imaging. Its administration as a continuous IV infusion, which produces optimal cardioprotection from reperfusion injury, has not been studied clinically. Thus the current proposal provides for the conduct of a safety, pharmacokinetic, and pharmacodynamic study of ATL-146e when given as a continuous infusion in healthy volunteers. Specifically we will study ATL-146e given as a continuous IV infusion to human volunteers also treated with a low IV bolus of endotoxin to establish the following: 1) safety and tolerability; 2) pharmacokinetics of ATL-146e and its primary metabolite including steady state levels and time to steady state; and 3) pharmacodynamic effects, (based on its ability to inhibit transient production of proinflammatory cytokines that occur in response to endotoxin). Collectively, the data derived from this study will provide the foundation for the conduct of a subsequent pilot Phase II clinical trial supported by the Phase 2 portion of this SBIR Fast-Track application that will be conducted in patients with AMI. This pilot Phase II study will then be used as a basis for a definitive Phase II clinical trial, followed by a definitive Phase III clinical trial and eventual market approval.